Process for trans-4-amino-1-cyclohexanecarboxilic acid derivatives

ABSTRACT

A process for the preparation of Compound (I) comprising reacting Compound (II) with a base in an aprotic solvent, which is represented by the following scheme:  
                 
 
wherein R 1  and R 2  are each independently lower alkyl.

TECHNICAL FIELD

The present invention relates to a process for the preparation oftrans-4-amino-1-cyclohexanecarboxilic acid derivatives which are usefulas intermediates of medicaments such as NPYY5 receptor antagonists andthe like.

BACKGROUND ART

Trans-4-amino-1-cyclohexanecarboxilic acid derivatives are useful asintermediates of medicament etc. For example,trans-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylic acid andthe like are disclosed as intermediates of NPYY5 receptor antagonists inthe following Patent Literature 1. However, an isolation yield of thetrans isomer is only 40% by the process described in the literaturebecause the cis isomer does not smoothly isomerize to the trans isomereven if it is reacted for many hours. Therefore, the process is notnecessarily satisfying as a process for a mass-production of the transisomer.

A development of a convenient process for the preparation oftrans-4-amino-1-cyclohexanecarboxylic acid has been desired in order toefficiently mass-produce various trans isomers of amino derivativesand/or carboxyl derivatives from 4-amino-1-cyclohexane carboxylic acid.

Patent Literature WO01/37826

DISCLOSURE OF INVENTION

An object of the present invention is to provide an efficient processfor the preparation of trans-4-amino-1-cyclohexanecarboxylic acidderivatives.

BEST MODE FOR CARRYING OUT THE INVENTION

As a result of various studies of an isomerization ofcis-4-amino-1-cyclohexanecarboxylic acid to the trans isomer, theinventors of the present invention found that the isomerization rate andisolation yield are remarkably increased by using a specific solvent orcrystallization solvent, or introducing a specific substituent on anamino group, and the following invention is completed.(1) A process for the preparation of a compound of the formula:

wherein R¹ and R² are each independently lower alkyl,comprising reacting a compound of the formula:

wherein each symbol is the same as defined above,with a base in an aprotic solvent.(2) The process as described in the above (1) comprising recrystallizingCompound (I) in an aprotic solvent.(3) The process as described in the above (1) or (2) wherein the aproticsolvent is a nonpolar aprotic solvent.(4) The process as described in the above (3) wherein the aproticsolvent is toluene.(5) The process as described in any one of the above (1) to (4) whereinthe base is selected from a group of an alkaline metal lower alkoxide,an alkaline metal halide and an alkaline metal amide.(6) The process as described in the above (5) wherein the base isalkaline metal lower alkoxide.(7) The process as described in any one of the above (1) to (6) whereinthe compound of the formula:

wherein R¹ and R² are each independently lower alkyl, is prepared byreacting a compound of the formula:

wherein R² is lower alkyl, with a compound of the formula:

wherein R¹ is lower alkyl to obtain a compound of the formula:

wherein each symbol is the same as defined above, and by oxidizingCompound (III).(8) A process for the preparation of a compound of the formula:

wherein R¹ is the same as defined above, comprising hydrolyzing Compound(I) obtained by the process as described in any one of the above (1) to(7).(9) The process as described in the above (8) comprising hydrolyzingCompound (I) which is not isolated from a reaction solution.(10) The process as described in any one of the above (1) to (9) whereinR¹ is t-butyl and R² is methyl.(11) A process for the preparation of a compound of the formula:

wherein R² is lower alkyl and R³ is optionally substituted phenyl,comprising reacting a compound of the formula:

wherein R² is the same as defined above with a compound of the formula:R³—CHO  (VI)wherein R³ is the same as defined above to obtain a compound of theformula:

wherein each symbol is the same as defined above, and reacting Compound(VII) with a base in an organic solvent.(12) The process as described in the above (11) wherein R³ isnitrophenyl.(13) A process for the preparation of a compound of the formula:

wherein R² is the same as defined above, comprising hydrolyzing Compound(VIII) obtained by the process described in the above (11) or (12).(14) A process for the preparation of a compound of the formula:

wherein R¹ and R² are each independently lower alkyl, comprisingreacting a compound of the formula:

wherein R² is the same as defined above, with a compound of the formula:

wherein R¹ is the same as defined above to obtain a compound of theformula:

wherein each symbol is the same as defined above, and oxidizing Compound(X).(15) The process as described in the above (14) wherein Compound (IX) isobtained by the process described in the above (11).(16) A process for the preparation of a compound of the formula:

wherein R¹ is lower alkyl, comprising hydrolyzing Compound (I) obtainedby the process described in the above (14) or (15).(17) A compound of the formula:

wherein R² is lower alkyl and R³ is optionally substituted phenyl.(18) A compound of the formula:

wherein R² is lower alkyl and R³ is optionally substituted phenyl.(19) A compound of the formula:

wherein R² is lower alkyl.(20) A compound of the formula:

wherein R¹ and R² are each independently lower alkyl.(21) A process for the preparation of a compound of the formula:

wherein R¹ is lower alkyl, R⁴ is hydrogen or lower alkyl, and Z isoptionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted amino, optionally substituted loweralkoxy, optionally substituted carbocyclyl or optionally substitutedheterocyclyl, prodrug, pharmaceutically acceptable salt or solvatethereof comprising reacting Compound (I′) obtained by any one of theprocesses described in the above (1) to (16) with a compound of theformula:R⁴NH-Z  (XI)wherein R⁴ and Z are the same as defined above.

The process of the present invention is described in detail below.(Process 1) Conversion of Compound (II) to Compound (I′)

wherein each symbol is the same as defined above.(Step 1)

Compound (I) can be obtained by reacting cis Compound (II) with a basein a nonpolar aprotic solvent. In the process, cis Compound (II) isisomerized to a trans isomer.

R¹ and R² of Compound (I) are each independently lower alkyl.

Lower alkyl includes a straight or a branched C1 to C6 alkyl andexamples are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl andn-hexyl.

R¹ is preferably C3 to C5 alkyl and more preferably t-butyl.

R² is preferably C1 to C4 alkyl or C1 to C3 alkyl, more preferablymethyl or ethyl and most preferably methyl.

The base is not limited as long as it efficiently proceeds to isomerizea cis isomer to a trans isomer, and preferably an alkaline metal loweralkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide,potassium ethoxide and potassium tert-butoxide; an alkaline metal halidesuch as NaH; and an alkaline metal amide such as lithium diisopropylamide (LDA), and NaNH₂. An alkaline metal lower alkoxide is morepreferable and sodium methoxide is most preferable.

The amount of the base is preferably about 1 to 5 mole equivalent andmore preferably about 2 to 3 mole equivalent relative to the amount ofCompound (II).

The aprotic solvent is not limited as long as it efficiently proceeds toisomerize a cis isomer to a trans isomer, and a nonpolar solvent and apolar solvent are exemplified. Preferable solvent is one in which atrans isomer, i.e. Compound (I) can be more efficiently crystallizedafter the reaction than a cis isomer, i.e. Compound (II). Examples of anpolar aprotic solvent are acetone, tetrahydrofuran and ethyl acetate.Examples of a nonpolar aprotic solvent are aromatic carbohydrates suchas benzene, toluene and xylene; aliphatic carbohydrates such asn-hexane; and ethers such as diethyl ether. A nonpolar aprotic solventis preferable and an aromatic carbohydrate is more preferable andtoluene is most preferable.

Reaction temperature is not limited but generally about 50 to 150° C.,and preferably about 80 to 110° C.

Reaction time is not limited but generally 1 to 50 hours and preferablyabout 1 to 3 hours.

The feature of the reaction is to produce trans Compound (I) byisomerizing cis Compound (II). The invention also includes a reactionfor isomerizing a cis isomer in a mixture of a cis isomer and a transisomer to a trans isomer and arising a ratio of the trans isomer in themixture. The isomerization rate is 90% or more, preferably 95% or more,and most preferably 97 to 100%. The isomerization rate in thespecification means the mole ratio of the trans isomer relative to totalmole of the cis isomer and the trans isomer after the reaction iscompleted, and it can be measured by a liquid chromatography or thelike.

Compound (I) can be obtained in a high yield by this reaction becausecis Compound (II) is efficiently isomerized to a trans isomer and atrans isomer is selectively crystallized.

Compound (I) is preferably recrystallized and examples of a solvent forrecrystallization are the same as mentioned above. Even if theaforementioned isomerization rate is less than 100%, trans Compound (I)can be obtained in 100% yield by this recrystallization step.

(Step 2)

Compound (I′) can be synthesized by hydrolyzing Compound (I) obtained bythe above step.

Examples of a solvent are methanol, ethanol, acetonitrile, toluene andacetone, and methanol is preferable.

Reaction temperature is not limited but generally about 0 to 100° C. andpreferably about 0 to 30° C.

Reaction time is not limited but generally about 1 to 50 hours andpreferably about 1 to 2 hours.

Examples of a catalyst for this reaction are sodium hydroxide, potassiumhydroxide and lithium hydroxide and sodium hydroxide is preferable.

Hydrolysis of Compound (I) can be conducted using Compound (I) which isisolated from the reaction solution obtained by Step 1 or which is notisolated, and preferably conducted using Compound (I) which is notisolated.

When the processes from Compound (II) to Compound (I′) are continuouslyconducted in the same vessel, the yield of Compound (I′) can beincreased, for example, Compound (I′) is obtained from Compound (II) in90% or more.

Compound (I′) is useful as an intermediate of medicaments because it canbe utilized as an intermediate of various NPYY5 receptor antagonists byamidation of a carboxyl group.

(Synthesis of Starting Compound (II))

A process for the preparation of Compound (II) is not limited but it canbe preferably synthesized in the following method.

wherein R¹ and R² are the same as defined above.(Step 1)

Compound (III) is obtained by reacting Compound (IV) with Compound (V),if desired, in the presence of a base.

Examples of the base are alkylamine such as triethylamine,N-methylmorpholine, dimethylaniline and the like and pyridine, andtriethylamine is preferable.

Examples of a solvent is ethyl acetate, tetrahydrofuran,dimethylformamide and toluene, and ethyl acetate is preferable.

Reaction temperature is not limited but generally about 0 to 50° C. andpreferably about 5 to 10° C.

Reaction time is not limited but generally about 1 to 50 hours andpreferably about 13 hours.

(Step 2)

Compound (II) is obtained by oxidizing Compound (III).

Examples of an oxidant are a hydrogen peroxide solution, peracetic acid(with ammonium molybdate tetrahydrate ((NH₄)₆Mo₇O₂₄ 4H₂O) or sodiumtungstate as a catalyst) and m-chloroperbenzoic acid, and a hydrogenperoxide solution (with ammonium molybdate tetrahydrate as a catalyst)is preferable.

Examples of a solvent are dimethylformamide, tetrahydrofuran,dimethylformamide and ethyl acetate, and dimethylformamide ispreferable.

Reaction temperature is not limited but generally about 0 to 100° C. andpreferably about 30 to 70° C.

Reaction time is not limited but generally 1 to 50 hours and preferablyabout 2 to 8 hours.

Compound (IV) may be a mixture of a cis isomer and a trans isomer. Ifthe obtained compound in this step is a mixture of a cis isomer(Compound (II)) and a trans isomer, the mixture can be subjected to aconversion reaction to Compound (I) itself as mentioned above.(Process 2) Conversion of Compound (IV) to Compound (IX)

wherein R² is lower alkyl and R³ is optionally substituted phenyl.(Step 1)

Compound (VII) is obtained by reacting Compound (IV) with Compound (VI),if desired, in the presence of a base.

Examples of the base are an alkylamine such as triethylamine, pyridine,N-methylmorpholine and dimethylaniline, and triethylamine is preferable.

Examples of a solvent are acetonitrile, ethyl acetate, tetrahydrofuranand dioxane, and acetonitrile is preferable.

Reaction temperature is not limited but generally about 0 to 100° C. andpreferably about 10 to 30° C.

Reaction time is not limited but generally 1 to 50 hours and preferablyabout 2 to 5 hours.

R³ of Compound (VI) is optionally substituted phenyl. Substituents areexemplified by 1 to 3 substituents, preferably one substituentindependently selected from the group of nitro, halogen such as F, Cl,Br and I, alkoxy, alkyl and amide. Nitro is preferable. Thesesubstituents may be substituted at any position on the phenyl ring andpreferably at p-position.

(Step 2)

Compound (VIII) is obtained by reacting Compound (VII) with a base in anorganic solvent. A cis isomer of a cyclohexane ring of Compound (VII) isisomerized to a trans isomer by this reaction.

A base is not limited as long as it can proceed with an isomerization ofthe cis isomer to the trans isomer and preferably exemplified by analkaline metal lower alkoxide such as sodium methoxide, sodium ethoxide,potassium methoxide, potassium ethoxide and potassium tert-butoxide, analkaline metal halide such as NaH, an alkaline metal amide such aslithium diisopropylamide (LDA) and NaNH₂. An alkaline metal loweralkoxide is preferable and sodium methoxide is more preferable.

The amount of a base is preferably about 1 to 10 mole equivalents andpreferably about 2 to 3 mole equivalents relative to Compound (VII).

An organic solvent is not limited as long as it efficiently proceed toisomerize the cis isomer to the trans isomer. A preferable solvent isone in which a trans isomer, i.e. Compound (VIII) can be moreefficiently crystallized than a cis isomer, i.e. Compound (VII).Examples of such solvent are above-mentioned aprotic solvent or alcoholsuch as methanol and ethanol, and methanol is more preferable.

Reaction temperature is not limited but generally about 25 to 100° C.,and preferably about 40 to 70° C.

Reaction time is not limited but generally 1 to 50 hours and preferablyabout 3 to 5 hours.

Compound (VII) may be a mixture of a cis isomer and a trans isomer at anarbitrary ratio. This reaction gives Compound (VIII) in high yieldbecause the cis isomer of Compound (VII) is efficiently isomerized tothe trans isomer and the trans isomer is selectively precipitated.Isomerization rate is 90% or more, preferably 95% or more, and morepreferably 98 to 100%. Compound (VII) wherein R³ is p-nitrophenyl can beefficiently isomerized to the trans isomer by this step to give Compound(VIII).

Compound (VIII) is preferably recrystallized and examples of a solventfor recrystallization are the same as mentioned above. Even if theaforementioned isomerization rate is less than 100%, trans Compound(VIII) can be obtained in 100% by this recrystallization step.

(Step 3)

Compound (IX) is obtained by hydrolysis of Compound (VIII).

Examples of a solvent are ethyl acetate, acetonitrile,dimethylformamide, methanol and ethanol, and ethyl acetate ispreferable.

Reaction temperature is not limited but generally about 0 to 50° C. andpreferably about 10 to 30° C.

Reaction time is not limited but generally 1 to 50 hours and preferablyabout 2 to 5 hours.

Examples of a catalyst for this reaction are HCl, H₂SO₄, acetic acid,CF₃COOH, toluenesulfonic acid and p-toluenesulfonic acid, and preferablyp-toluenesulfonic acid.

According to this step, Compound (IX), i.e., a trans isomer of Compound(IV), can be easily obtained by imidating Compound (IV), followed byisomerizing. Compound (IX) is useful as an intermediate of a medicamentbecause it is easily utilized as an intermediate to produce NPYY5receptor antagonists having various substituents which are oncyclohexane ring with trans configuration (referring to the above PatentLiterature 1) by chemical modifications such as amidation of an estergroup and/or sulfonylation of an amino group. Therefore, the aboveCompound (VII) and Compound (VIII) are also useful as intermediates.(Process 3) Conversion of Compound (IX) to Compound (I)

wherein each symbol is the same as defined above.(Step 1)

Compound (X) is obtained by reacting Compound (IX) with Compound (V), ifdesired, in the presence of a base. This step may be performed accordingto the above-mentioned step for synthesis of Compound (IIII) fromCompound (IV).

Any base can be used and examples are alkylamine such as triethyl amine,pyridine, N-methyl morpholine and dimethylaniline. Triethylamine ispreferable. The amount of a base is preferably about 2.0 to 3.0 moleequivalent relative to Compound (IX).

The amount of Compound (V) is preferably about 1.0 to 1.5 moleequivalent relative to Compound (IX).

Any solvent can be used provided that it can dissolve or suspend areaction substrate to give a reactive solution or slurry. Examples of asolvent are ethyl acetate, tetrahydrofuran, dimethylformamide andtoluene and preferably ethyl acetate or dimethylformamide. The arbitraryamount of a solvent can be used as long as the reaction can be performedin the solution or slurry. For example, a solvent is preferably 1 to 10times of volume relative to the total volume of a substrate and morepreferably 3 times of volume (cc) relative to total weight (g) of asubstrate.

Reaction temperature is not limited but generally about −10 to 50° C.,preferably about 5 to 10° C.

Reaction time is not limited but generally about 1 hour to 5 days,preferably 1 hour to 2 days and more preferably about 1 to 3 hours.

Thus obtained product may be isolated or purified, or may be used forthe next step without isolation or purification. The use of the productwithout isolation or purification is advantageous because the next stepcan be continuously performed.

(Step 2)

Compound (I) is obtained by oxidizing Compound (X). This step isperformed according to the above step for synthesis of Compound (II)from Compound (III). Examples of an oxidant are a hydrogen peroxidesolution, peracetic acid (with ammonium molybdate tetrahydrate((NH₄)₆Mo₇O₂₄ 4H₂O) or sodium tungstate or hydrate as a catalyst) andm-chloroperbenzoic acid and a hydrogen peroxide solution (with ammoniummolybdate tetrahydrate ((NH₄)₆Mo₇O₂₄ 4H₂O) as a catalyst) is preferable.

The amount of a catalyst is preferably about 0.01 to 0.05 moleequivalent relative to Compound (X″). The amount of a peroxide ispreferably about 1.0 to 2.0 mole equivalents relative to Compound (X″).

Any solvent can be used provided that it can dissolve or suspend areaction substrate to give a reactive solution or slurry. Examples of asolvent are dimethylformamide, tetrahydrofuran and ethyl acetate, andpreferably dimethylformamide.

The arbitrary amount of a solvent can be used as long as the reactioncan be carried out in the solution or slurry. For example, a solvent ispreferably 1 to 10 times of volume relative to the total volume of asubstrate and more preferably 3 times of volume (cc) relative to totalweight (g) of a substrate.

Reaction temperature is not limited but generally about 0 to 100° C. andpreferably about 20 to 80° C.

Reaction time is not limited but generally about 1 hour to 5 days,preferably 1 hour to 2 days and more preferably about 2 to 8 hours.

Thus-obtained Compound (I) can be converted to Compound (I′) byhydrolysis according to the above.(Process 4)

wherein R is hydrogen or a carboxyl-protective group and other eachsymbol is the same as defined above.(Step 1)

In this step, if desired, Compound (IX′) is protected by a protectivegroup R to give Compound (IX″), i.e., a protected trans cyclohexanecarboxylic acid compound. If the next reaction is not influenced by thesubstituents, a protective group R need not to be introduced and a freecarboxylic acid compound may be subjected to Step 2.

A carboxyl-protective group is not limited as long as it is usually usedand Examples are methyl, ethyl, t-butyl, phenyl, benzyl andtriphenylmethyl. If methyl is used as a protective group, Compound (IX″)can be obtained by reacting Compound (IX′) with a thionyl chloride inmethanol.

The amount of Compound (V) is about 0.6 to 2.0 mole equivalent relativeto Compound (IX′).

Any solvent can be used provided that it can dissolve or suspend areaction substrate to give a reactive solution or slurry.

The arbitrary amount of a solvent can be used as long as the reactioncan be performed in the solution or slurry. For example, a solvent ispreferably 1 to 10 times of volume relative to the total volume of asubstrate and more preferably 3 times of volume (cc) relative to totalweight (g) of a substrate.

Reaction temperature is preferably 0 to 60° C.

As a method for isolation of the product after the reaction, carryingout the crystallization is preferable and acetonitrile or toluene ispreferably used as a solvent.

Reaction time is preferably about 1 hour to 5 days and more preferablyabout 2 hours to 2 days.

Thus obtained product may be isolated or purified, and the productwithout isolation or purification may be subjected to the next step. Theuse of the product without isolation or purification is advantageousbecause the next step can be continuously performed.

(Step 2)

In this step, Compound (X″) is obtained by reacting Compound (IX″) withCompound (V) and a base.

Reaction conditions are the same as those in the above Process 3, Step1.

(Step 3)

In this step, Compound (I″) is obtained by oxidizing Compound (X″).

Reaction conditions are the same as those in the above Process 3, Step2.

Thus-obtained product may be isolated or purified. The product withoutisolation or purification may be subjected to the next step. The usewithout isolation or purification is advantageous because the next stepcan be continuously performed.

Compound (I″) wherein R is hydrogen need not to be subjected to the nextstep and can be converted to Compound (XII) according to Process 5mentioned below.

(Step 4)

In this step, Compound (I′) is obtained by deprotective Compound (I″)wherein R is a carboxyl-protective group.

It is preferred to use an appropriate reagent to deprotect theprotective group introduced in Step 1.

For example; when methyl is used as a protective group, Compound (I″)may be reacted with a base such as sodium methoxide and water. Theamount of a base is preferably about 2.0 to 3.0 mole equivalent relativeto Compound (I″).

Any solvent can be used provided that it can dissolve or suspend areaction substrate to give a reactive solution or slurry.

The arbitrary amount of a solvent can be used as long as the reactioncan be performed in the solution or slurry. For example, a solvent ispreferably 1 to 10 times of volume relative to the total volume of asubstrate.

Reaction temperature is preferably 0 to 40° C.

Reaction time is preferably about 1 hour to 5 days and preferably about2 hours to 24 hours.

Thus-obtained product may be isolated or purified. The product withoutisolation or purification may be subjected to the next step. The usewithout isolation or purification is advantageous because the next stepcan be continuously performed.(Process 5) Conversion of Compound (I′) to Compound (XII)

wherein R¹ is lower alkyl; R⁴ is hydrogen or lower alkyl; Z isoptionally substituted lower alkyl, optionally substituted loweralkenyl, optionally substituted amino, optionally substituted loweralkoxy, optionally substituted carbocyclyl, or optionally substitutedheterocyclyl.

Examples of lower alkyl of R⁴ are the same as those represented by R¹.R⁴ is preferably hydrogen.

Examples of the substituent in “optionally substituted lower alkyl” of Zare (1) halogen; (2) cyano; (3) the following groups (i) to (xvi): (i)hydroxy, (ii) lower alkoxy, (iii) mercapto, (iv) lower alkylthio, (v)acyl, (vi) acyloxy, (vii) carboxy, (viii) lower alkoxycarbonyl, (ix)imino, (x) carbamoyl, (xi) thiocarbamoyl, (xii) lower alkyl carbamoyl,(xiii) lower alkylthio carbamoyl, (xiv) amino, (xv) lower alkylamino or(xvi) heterocyclylcarbonyl, which may be optionally substituted by atleast one of groups selected from the Substituent Group β defined below.

Substituent Group α is a group of (1) halogen; (2) oxo; (3) cyano; (4)nitro; (5) imino optionally substituted by lower alkyl or hydroxy; (6)the following groups (i) to (xxi): (i) hydroxy, (ii) lower alkyl, (iii)lower alkenyl, (iv) lower alkoxy, (v) carboxyl, (vi) loweralkoxycarbonyl, (vii) acyl, (viii) acyloxy, (ix) imino, (x) mercapto,(xi) lower alkylthio, (xii) carbamoyl, (xiii) lower alkyl carbamoyl,(xiv) cycloalkylcarbamoyl, (xv) thiocarbamoyl, (xvi) loweralkylthiocarbamoyl, (xvii) lower alkylsulfinyl, (xviii) loweralkylsulfonyl, (xix) sulfamoyl, (xx) lower alkylsulfamoyl and (xxi)cycloalkylsulfamoyl, which may be optionally substituted by at least oneof groups selected from Substituent Group β; (7) the following groups(i) to (v): (i) cycloalkyl, (ii) cycloalkenyl, (iii) cycloalkyloxy, (iv)amino and (v) alkylenedioxy, which may be optionally substituted by asubstituent selected from the group of Substituent β, lower alkyl, loweralkoxy-lower alkyl, optionally protected hydroxy-lower alkyl; and (8)the following groups: (i) phenyl, (ii) naphtyl, (iii) phenoxy, (iv)phenyl-lower alkoxy, (v) phenylthio, (vi) phenyl-lower alkylthio, (vii)phenylazo, (viii) heterocyclyl, (ix) heterocyclyloxy, (x)heterocyclylthio, (xi) heterocyclylcarbonyl and (xii)heterocyclylsulfonyl, which may be optionally substituted by asubstituent selected from the group of Substituent β, lower alkyl,halogeno-lower alkyl and/or oxo.

Substituent Group β is a group of halogen, optionally protected hydroxy,mercapto, lower alkoxy, lower alkenyl, amino, lower alkylamino, loweralkoxycarbonyl amino, lower alkylthio, acyl, carboxyl, loweralkoxycarbonyl, carbamoyl, cyano, cycloalkyl, phenyl, phenoxy, loweralkyl phenyl, lower alkoxy phenyl, halogenophenyl, naphtyl andheterocyclyl.

“Lower alkenyl” includes C2 to C10, preferably C2 to C8 and morepreferably C₃ to C₆ straight or branched alkenyl which has at least onedouble bond at arbitrary position. Examples are vinyl, propenyl,isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl,isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl,octenyl, nonenyl, and decenyl. Substituents in “optionally substitutedlower alkenyl” are exemplified by halogen, lower alkoxy, lower alkenyl,amino, lower alkylamino, lower alkoxycarbonyl amino, lower alkylthio,acyl, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, cycloalkyl,phenyl, lower alkyl phenyl, lower alkoxy phenyl, naphtyl and/orheterocyclyl.

Substituents in “optionally substituted amino” are exemplified by theabove-mentioned substituent selected from Substituent Group β,optionally substituted benzoyl and/or optionally substitutedheterocyclylcarbonyl wherein the substituents are hydroxy, lower alkyl,lower alkoxy and/or lower alkylthio.

“Lower alkoxy” means oxy group combined with the above “lower alkyl” andexamples are methoxy, ethoxy and i-propoxy.

Substituents in “optionally substituted lower alkoxy” are exemplified byat least one of groups selected from the above Substituent Group β andpreferable examples are phenyl, lower alkyl phenyl, lower alkoxy phenyl,naphtyl or heterocyclyl.

“Carbocyclyl” includes “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and“aryl”.

“Cycloalkyl” includes C3 to C8 and preferably C5 or C6 cyclic alkyl.Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

“Cycloalkenyl” includes groups which have at least one double bond atarbitrary position in the above cycloalkyl and examples arecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl andcyclohexadienyl.

“Bicycloalkyl” includes C5 to C8 alicyclic groups wherein the two ringsshare two or more atoms and which are given by removing one hydrogenfrom C5 to C8 alicyclic group. Examples are bicyclo[2.1.0]pentyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.

“Aryl” means monocyclic or polycyclic aromatic carbocyclic group andincludes phenyl, naphtyl, anthryl, and phenanthryl. “Aryl” includes arylwhich is fused with another non-aromatic carbocycle and it isexemplified by indanyl, indenyl, biphenylyl, acenaphtyl,tetrahydronaphtyl and fluorenyl. Phenyl is preferable.

Examples of substituents in “optionally substituted carbocyclyl” are atleast one of groups selected from the group of the above SubstituentGroup α and Substituent Group β. “Carbocyclyl” may be substituted withthem at any arbitrary positions.

“Heterocyclyl” includes heterocyclic groups which contain at least onehetero atoms arbitrarily selected from the group of O, S and N, andexamples are 5 to 6 membered heteroaryl such as pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl,triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl, thiadiazolyl, furyl and thienyl; fused bicyclic heterocyclylsuch as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl,isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl,benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl,triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl,dihydropyridyl, tetrahydroquinolyl and tetrahydrobenzothienyl; fusedtricyclic heterocyclyl such as carbazolyl, acridinyl, xanthenyl,phenothiazinyl, phenoxatiinyl, phenoxazinyl and dibenzofuryl;non-aromatic heterocyclyl such as dioxanyl, thiiranyl, oxiranyl,oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl,piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,dihydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyland tetrahydroisothiazolyl.

Heterocyclyl which is fused with a ring other than heterocyclic ringsuch as benzothiazolyl may have a bonding radical on any ring.

Examples of the substituent in “optionally substituted heterocyclyl” arethe same as those carbocyclyl.

Compound (XII), a prodrug or a pharmaceutically acceptable salt orsolvate thereof can be obtained by reacting Compound (I′) with Compound(XI). This reaction can be performed according to amidation reactiondescribed in the above Patent Literature 1 or the like.

Generally, Compound (I′) is reacted with an activated Compound (XI) suchas a corresponding acid halide (eg. reaction with thionyl chloride,oxalyl chloride or phosphorus oxychloride), a corresponding acidanhydride, a corresponding activated ester or the like at about 0° C. to100° C. for about 3 minutes to 10 hours. Tetrahydrofuran,dimethylformamide, diethyl ether, dichloromethane, toluene, benzene,xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate,pentane, heptane, dioxane, acetone, acetonitrile, water or the mixturethereof can be used as a solvent, and toluene or tetrahydrofuran ispreferable. If necessary, a base (triethylamine or pyridine etc.),thionyl chloride, an acid halide (such as thionyl chloride, oxalylchloride or phosphorus oxychloride), an acid anhydride or an activatedester can be used as an activating agent.

As alternative process, Compound (I′) is reacted with Compound (XI) in asuitable solvent (such as tetrahydrofuran, dimethylformamide, diethylether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane,chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane,acetone, acetonitrile, water or the mixture thereof) in the presence ofa condensing agent at about 0° C. to 100° C. for about 3 minutes to 10hours to obtain a target compound. As a condensing agent,1,1-carbonyldiimidazole, dicyclohexylcarbodiimide or water-solublecarbodiimide (1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide) and thelike can be used.

Compound (XII) is useful as, for example, a NPYY5 receptor antagonist.

Examples of a pharmaceutically acceptable salt for Compound (XII) aresalts of a mineral acid such as hydrochloric acid, sulfuric acid, nitricacid, phosphoric acid; salts of an organic acid such asparatoluenesulfonic acid, methansulfonic acid, oxalic acid and citricacid; salts of an organic base such as ammonium, trimethylammonium andtriethylammonium; salts of an alkaline metal such as sodium, potassiumand the like and salts of an alkaline earth metal such as calcium,magnesium and the like. Examples of solvate of Compound (XII) arehydrate, alcoholate and the like. A prodrug of Compound (XII) meansderivatives which can be converted to Compound (XII) by chemicaldecomposition or metabolism. Methods for selecting or producingappropriate prodrugs are described in Design of Prodrugs, Elsevier,Amsterdam 1985, for example.

The present invention provides each step of the above-mentionedprocesses, all of the processes comprising combination of the stepsarbitrarily selected, and intermediates of such processes.

EXAMPLES

The present invention is further explained by the following Examples.Abbreviations in Examples mean as follows:

Me: methyl

Et: ethyl

Ac: acetyl

DMF: dimethylformamide

THF: tetrahydrofuran

p-TsOH: para-toluenesulfonic acid

WSCD: water-soluble carbodiimide

BtOH: N-hydroxybenzotriazole

Reference Example 1 Synthesis of 2-methylpropane-2-sulfinylchloride (3)(1) 2-Methylpropane-2-sulfinic acid (2)

Sulfurous acid gas (162 g, 1.23 eq) was introduced into a solution oft-butyl magnesium chloride (1) in tetrahydrofuran (2 mol/L, 1 kg, 2.06mol) with cooling at 2 to 20° C. Two lots obtained in the same mannerwere combined, poured into a mixture of ice, concentrated hydrochloricacid and toluene, and extracted. Toluene layer was washed with saturatedbrine and each of aqueous layer was extracted with toluene. Toluenelayers were dried over sodium sulfate, concentrated under reducedpressure to obtain a solid residue of (2) (396 g, 78.7%).

(2) 2-Methylpropane-2-sulfinyl chloride (3)

Thionyl chloride (460 mL) was added dropwise to a solution of (2) (700g, 5.729 mol) in anhydrous tetrahydrofuran (3 L) at ice cooling and themixture was stirred for 30 minutes at the same temperature. The reactionmixture was concentrated under reduced pressure to obtain a solidresidue (3) (900 g).

¹H NMR (CDCl₃): δ 1.41 (s, 3H)

(3) Tert-butyl tert-butane thiosulfinate (5)

30% hydrogen peroxide solution (128 mL) was added dropwise to a solutionof tert-butyl disulfide (4) (178.36 g, 1 mol) in acetic acid (357 mL)over 38 minutes at 30 to 37° C. After the mixture was stirred for 3hours at same temperature, 7.5% aqueous solution of sodium sulfite (900mL) was added over 19 minutes at 6 to 13° C. Ethyl acetate (1.3 L) wasadded to the reaction mixture and the mixture was extracted twice.Separated organic layer was neutralized with aqueous solution of analkaline and washed with water. The solvent was concentrated underreduced pressure to obtain (5) (190.4 g, 98%).

¹H NMR (CDCl₃): δ 1.38 (s, 3H), 1.56 (s, 3H)

(4) 2-Methylpropane-2-sulfinyl chloride (3)

a) Chlorine gas (65 g, 1.1 eq) was introduced into tert-butyltert-butane thiosulfinate (5) (190.4 g, 0.84 mol) at 11 to 20° C. Themixture was stirred for 30 to 120 minutes at room temperature anddistilled under reduced pressure to obtain (3) (bp.13 mmHg 7-13, 34-35°C., 105.7 g, 90%)

¹H NMR (CDCl₃): δ 1.41 (s, 3H)

b) Chlorine gas (77 g, 1.1 eq) was introduced into a solution oftert-butyl tert-butane thiosulfinate (5) (162.5 g, 0.98 mol) indichloromethane (665 mL) at 11 to 20° C. Dichloromethane wasconcentrated under reduced pressure and the obtained residue wasdistilled under reduced pressure to obtain (3) (bp.18 mmHg 7-13, 50-56°C., 130.0 g, 94.3%).

Reference Example 2 Synthesis of methyl cis-4-amino-1-cyclohexanecarboxylate hydrochloride (7)

Thionyl chloride (301 mL, 0.6 eq) was added dropwise to a suspension ofcis-4-amino-1-cyclohexane carboxylic acid (6) (984 g, 6.87 mol) inmethanol (4.82 L) and stirred for 6 hours at room temperature, and themixture was allowed to be stand for 3 days. The reaction mixture wasconcentrated under reduced pressure and isopropyl ether was added to themixture. The appeared crystals were collected by filtration to obtainmethyl cis-4-amino-1-cyclohexane carboxylate hydrochloride (1086 g,81.6%). The mother liquor was concentrated under reduced pressure andmethanol (50 mL) and isopropyl ether (1.0 mL) were added to the residue.The appeared crystals were collected by filtration to obtain secondcrystals of (7) (94 g, 7.0%).

mp. 172-174° C.,

Anal. Calcd for C₈H₁₆NO₂Cl C, 49.61; H, 8.33; N, 7.23; Cl, 18.31. FoundC, 49.17; H, 8.27; N, 7.33; Cl, 18.19. H₂O>0.1%

1H NMR (CD₃OD): δ 1.40-1.50 (m, 4H), 1.85-1.95 (m, 2H), 2.03-2.20 (m,2H), 2.70-2.75 (m, 1H), 3.10-3.25 (m, 1H), 3.70 (s, 3H)

Example 1 Synthesis of methyltrans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (12)(via Compound (15)) (1) Methylcis-4-(2-methylpropane-2-sulfinylamino)cyclohexane carboxylate (14)

Triethylamine (272 mL) was added dropwise to a suspension of methylcis-4-amino-1-cyclohexane carboxylate hydrochloride (7) (151 g, 0.78mol) and 2-methylpropane-2-sulfinyl chloride (3) (120.8 g, 1.1 eq) inethyl acetate (755 mL) at 6 to 9° C. The mixture was stirred for an hourat the same temperature and poured into diluted hydrochloric acid. Themixture was extracted with ethyl acetate (750 mL×2) and each of organiclayers was washed with water, 5% aqueous solution of sodium bicarbonate,water and brine, successively. The solvent was concentrated underreduced pressure to obtain oily (14) (222.7 g, 109%).

(2) Methyl cis-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylate (15)

After an aqueous solution of ammonium molybdate tetrahydrate (28.9 g,0.03 eq) (100 mL) was added to a solution of (14) (222.7 g) in DMF (1.0L), 30% hydrogen peroxide solution (177 g, 2 eq) was added dropwise tothe mixture over 30 minutes at 30 to 43° C. The mixture was stirred for2 hours at the same temperature and poured into water (10 L). Themixture was stirred with cooling and the appeared crystals werecollected by filtration. After the crystals were dissolved in ethylacetate (1.8 L), the solution was dried over magnesium sulfate etc. andconcentrated under reduced pressure. Isopropyl ether was added to theresultant and the appeared crystals were collected by filtration anddried to obtain (15) (171.2 g, 79% yield from (7)).

mp. 162-4° C.,

Anal. Calcd for C₁₂H₂₃NO₄S C, 51.96; H, 8.36; N, 5.05; S, 11.56. FoundC, 51.80; H, 8.37; N, 5.00; S, 11.49. H20>0.1%

¹H NMR (CDCl₃): δ 1.39 (s, 3H), 1.60-2.00 (m, 8H), 2.45-2.55 (m, 1H),3.45-3.55 (m, 1H), 3.69 (s, 3H), 3.95 (d, J=12 Hz 1H)

(3) Methyl trans-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylate (12)

To a suspension of powder sodium methylate (7.06 g, 2.5 eq) in toluene(145 mL) was added methyl formate (1.61 mL, 0.5 eq). After the mixturewas stirred for an hour at room temperature, (15) (14.5 g, 52.3 mmol)was added to the mixture. The mixture was heated under reflux for 2hours 25 minutes, cooled and poured into 0.76 mol/L hydrochloric acid(344 mL). The mixture was extracted with ethyl acetate (300 mL×2), andthe obtained organic layer was washed with water and brine, and driedover sodium sulfate. The solvent was removed under reduced pressure toobtain 14.42 g of crystalline residue (cis:trans=3:97). The residue wasrecrystallized from toluene to obtain (12) (10.2 g, 70% from (15)).

Comparison Example 1 Isomerization of (15) to (12) in methanol

Methanol (75 mL) and methyl formate (4.44 mL, 0.5 eq) were added to 28%solution of sodium methylate in methanol (69.45 g, 2.5 eq). After themixture was stirred for an hour at room temperature, methylcis-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (15) (40g, 0.144 mol) was added to the mixture. The mixture was heated underreflux for 2 hours 20 minutes, cooled and poured into 1.2 mol/Lhydrochloric acid (600 mL). The appeared crystals were collected byfiltration (37.31 g, cis:trans=18:82).

24.81 g of the crystals were recrystallized from toluene to obtain 15 gof methyl trans-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylate (12) (56% yield from (15)).

mp, 141-143° C.,

Anal. Calcd for C₁₂H₂₃NO₄S C, 51.96; H, 8.36; N, 5.05; S, 11.56.

Found C, 51.67; H, 8.27; N, 5.02; S, 11.46. H₂O>0.1%

1H NMR (CDCl₃): δ 1.20-1.40 (m, 2H), 1.39 (s, 3H), 1.42-1.62 (m, 2H),2.0-2.32 (m, 5H), 3.20-3.35 (m, 1H), 3.67 (s, 3H), 3.99 (d, J=9 Hz, 1H)

Example 2 Synthesis oftrans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylic acid(13)

An aqueous solution (4.4 L) of sodium hydroxide (441 g, 2.5 eq) wasadded dropwise to a solution of methyltrans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (12)(1222 g, 4,407 mol) in methanol (2.45 L) over 30 minutes at 4 to 12° C.The mixture was stirred for an hour at 12 to 36° C. and methanol wasremoved under reduced pressure. The pH value of the residue was adjustedto 9.7 with hydrochloric acid and the mixture was washed with ethylacetate (4.5 L). The organic layer was extracted with water (1 L).Aqueous layers were combined, acidified with hydrochloric acid, andextracted with ethyl acetate (5 L, 4 L). Each of organic layer waswashed with brine, dried over sodium sulfate and concentrated underreduced pressure. The appeared crystals were collected by filtration andwashed with IPE to obtain (13) (1012 g, 87.2%).

mp. 201-203° C.,

Anal. Calcd for C₁₁H₂₁NO₄S C, 50.17; H, 8.04; N, 5.32; S, 12.18.

Found C, 49.88; H, 8.02; N, 5.32; S, 12.23.

¹H NMR (CDCl₃): δ 1.16-1.32 (m, 2H), 1.39 (s, 3H), 1.49-1.62 (m, 2H),2.0-2.32 (m, 5H), 3.27 (m, 1H), 3.67 (s, 3H), 3.99 (d, J=9 Hz, 1H)

Example 3 Synthesis oftrans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylic acid(13) (One-pot process from (15))

To a suspension of powder sodium methylate (48.69 g, 2.5 eq) in toluene(1.0 L), was added methyl formate (11.11 mL, 0.5 eq) and the mixture wasstirred for an hour at room temperature. To a mixture was added methyl4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (15) (100 g,0.361 mol). The mixture was heated under reflux for 2 hours 30 minutes(Notes: Compound (12) was precipitated at this time) and cooled to 40°C. Tetrabutylammonium bromide (5.81 g, 0.025 eq) and water (450 mL) wereadded to the mixture and the mixture was stirred for 1 hour 30 minutesat 35 to 40° C. Aqueous layer was separated and acidified withhydrochloric acid. The appeared crystals were collected by filtration,washed with water and dried to obtain (13) (87.8 g, 92.5% from (15)).

mp, 201-203° C.

¹H NMR (CDCl₃): δ 1.16-1.32 (m, 2H), 1.39 (s, 3H), 1.49-1.62 (m, 2H),2.0-2.32 (m, 5H), 3.27 (m, 1H), 3.67 (s, 3H), 3.99 (d, J=9 Hz, 1H)

Example 4 Synthesis of methyl trans-4-amino-1-cyclohexane carboxylatep-toluenesulfonate (10) (1) Methyl 4-(nitrobenzylideneaminocyclohexa)-carboxylate (8)

Triethylamine (848 mL, 1 eq) was added dropwise to a solution of methylcis-4-amino-1-cyclohexane carboxylate hydrochloride (8) (1178 g, 6.08mol) and p-nitrobenzaldehyde (919 g, 1 eq) in acetonitrile (5.89 L) andthe mixture was stirred for 3 hours at the same temperature. Thereaction mixture was concentrated under reduced pressure and theresultant was extracted with methyl acetate (7 L). The organic layer waswashed with water (7 L, 3 L) and saturated brine, successively, anddried over sodium sulfate and magnesium sulfate. The mixture wasconcentrated under reduced pressure and toluene (1 L) was added to theresidue. The mixture was concentrated under reduced pressure to obtaincrystalline residue (8) (2.2 kg).

(2) Methyl (S)-4-(nitrobenzylidene aminocyclohexa)-carboxylate (9)

Methanol (4 L) and methyl formate (188 mL, 0.5 eq) were added to 28%solution of sodium methylate in methanol (3.01 L, 2.5 eq) and themixture was stirred for 40 minutes at room temperature. A solution of(8) (2.2 kg, 6.06 mol) in methanol (1.6 L) was added to the mixture andthe mixture was heated under reflux at 50° C. for 4 hours. The reactionmixture was allowed to ice-cooling and the appeared crystals werecollected by filtration and washed with cooled methanol (1.6 L×2) toobtain (9) (1461 g, 82.7%).

mp. 176-177,

Anal. Calcd for C₁₅H₁₈N₂O₄ C, 60.05; H, 6.25; N, 9.65.

Found C, 61.79; H, 6.14; N, 9.76.

¹H NMR (CDCl₃): δ 1.5-1.7 (m, 4H), 1.8-2.1 (m, 4H), 2.3-2.4 (m, 1H),3.2-3.3 (m, 1H), 3.7 (s, 3H), 7.89, 8.26 (q, J=9 Hz, 4H), 8.4 (s, 1H)

(3) Methyl trans-4-amino-1-cyclohexane carboxylate p-toluene sulfonate(10)

Crystals of (9) (1460 g) were added to a mixture of p-toluenesulfonicacid monohydrate (1052 g, 1.1 eq), ethyl acetate (8 L) and water (511mL) at room temperature and the mixture was washed with ethyl acetate(2.2 L). The mixture was stirred for 1.5 hours at room temperature andpoured into cooled ethyl acetate (32 L). The appeared crystals werecollected by filtration and washed with ethyl acetate (2 L×2) to obtain(10) (1559 g, 94.1%).

mp. 183-185° C.,

Anal. Calcd for C₁₅H₂₃NO₅S C, 54.69; H, 7.04; N, 4.25; S, 9.73.

Found C, 54.36; H, 6.98; N, 4.51; S, 9.65.

¹H NMR (CDCl₃): δ 1.3-1.6 (m, 4H), 2.0-2.15 (m, 4H), 2.3 (m, 1H), 2.37(s, 3H), 3.05 (m, 1H), 3.3 (m, 1H), 3.66 (s, 3H), 7.70, 7.24 (q, J=8.1Hz, 4H)

Example 5 Synthesis of methyltrans-4-(2-methylpropane-2-sulfonylamino)cyclohexane carboxylate (12)(via Compound (11)) (1) Methyltrans-4-(2-methylpropane-2-sulfinylamino)cyclohexane carboxylate (11)

Triethylamine (1658 mL, 2.7 eq) was added dropwise to a solution of2-methylpropane-2-sulfinyl chloride (3) (900 g, 1.3 eq) and methyltrans-4-amino-1-cyclohexane carboxylate p-toluenesulfonate (10) (1452 g,4.407 mol) in tetrahydrofuran (9.5 L) with ice-cooling. The mixture wasstirred for 1.5 hours at room temperature, poured into water (9.5 L) andextracted with ethyl acetate (9.5 L, 5 L). Each of organic layer waswashed with brine twice, dried over sodium sulfate, and concentratedunder reduced pressure to obtain (11) (1.26 kg).

(2) Methyltrans-4-(2-methylpropane-2-sulfonylamino)cyclohexanecarboxylate (12)

An aqueous solution (576 mL) of ammonium molybdate tetrahydrate (163 g,0.03 eq) was added to a solution of (11) (1.26 kg) in DMF (5.76 L). Tothe mixture was added dropwise 30% hydrogen peroxide solution (749 g,1.5 eq) over 39 minutes at 25 to 44° C. The mixture was stirred for 47minutes at the same temperature and 30% hydrogen peroxide solution (250g, 0.5 eq) was added dropwise over 3 minutes at 38 to 39° C. The mixturewas stirred for 30 minutes at the same temperature, poured into icedwater (23 L), and stirred with cooling. The appeared crystals werecollected by filtration to obtain (12) (1222 g, 100% from (10)).

¹H NMR (CDCl₃): δ 1.20-1.7 (m, 4H), 1.39 (s, 3H), 2.00-2.15 (m, 2H),2.15-2.23 (m, 3H), 3.10-3.35 (m, 1H), 3.67 (s, 3H), 3.80 (d, J=12 Hz,1H)

Example 6

To the mixture of 27.0 kg of Compound (4) and 56.6 kg of glacial aceticacid was added dropwise 6.2 kg of 35% hydrogen peroxide solution withstirring over 65 minutes at 25° C. to 35° C. and the mixture was stirredfor 87 minutes at 32° C. to 35° C. To the mixture was added dropwise 6.2kg of 35% hydrogen peroxide solution with stirring over 60 minutes at32° C. to 34° C. and stirred for 82 minutes at 34° C. to 35° C. To themixture was added dropwise 6.2 kg of 35% hydrogen peroxide solution withstirring over 60 minutes at 35° C. to 36° C. and the mixture was stirredfor 135 minutes at 36° C. to 37° C. To the reaction mixture was added81.0 kg of water and 62.2 kg of 20% aqueous solution of sodiumhydrogensulfite was added dropwise to the mixture at 17° C. to 28° C. toremove remained peroxide. After the mixture was cooled to 9° C., 79.6 kgof 48% aqueous solution of sodium hydroxide was added dropwise to themixture over 136 minutes at 9° C. to 15° C. To the mixture was added73.1 kg of ethyl acetate and separated. The organic layer was washedwith 85.1 kg of 5% sodium hydrogencarbonate and 81.0 kg of water,successively. The first aqueous layer was washed with 24.4 kg of ethylacetate and the combined organic layer was concentrated to the extent of1.0% or less of ethyl acetate and 0.3% or less of water.

After the mixture was divided into 8 portions, 1.3 kg of chlorine gaswas introduced into one portion over 145 minutes at 9° C. to 17° C. Themixture was stirred for 100 minutes at 8° C. to 13° C. and distilledunder reduced pressure to obtain 2.45 kg of Compound (3) (92.1% fromdibutyldisulfide)

Example 7

After the mixture of 28.4 kg of DMF, 8.4 kg of butylsulfinyl chlorideand 10.6 kg of Compound (7) was cooled to −9° C., 12.7 kg oftriethylamine was added dropwise at −9° C. to 2° C. The mixture wasstirred for 60 minutes at 0° C. to 6° C. and 21.2 kg of water was added.To the mixture was added dropwise 3.5% aqueous solution of hydrochloricacid at 4° C. to 8° C.

A solution of 2.00 kg of ammonium heptamolybdate tetrahydrate in 10.40kg of water was added to the mixture and heated to 40° C. To the mixturewas added dropwise 8.0 kg of 35% hydrogen peroxide solution at 40° C. to45° C. and stirred for 130 minutes at 40° C. to 44° C. The reactionmixture was cooled to 22° C. and poured into the mixture of 7.4 kg ofsodium chloride, 7.4 kg of sodium sulfide, and 99.6 kg of water toremove remained peroxide. The mixture was stirred for 60 minutes at 25°C. to 30° C. and filtered with Buechner funnel. The filtrate was washedwith 13.8 kg of water three times. After wet crystals were separated,136.9 kg of ethyl acetate and 30.4 kg of water were added and themixture was heated to 39° C. After the crystals were dissolved, aqueouslayer was removed and ethyl acetate was concentrated to about 30 kg byremoving ethyl acetate. To the mixture was added 106.3 kg of cyclohexaneand the mixture was concentrated to about 90 kg and stirred for 90minutes at 26° C. to 28° C. After the appeared crystals were separated,they were washed with 11.8 kg of cyclohexane twice and dried underreduced pressure at 50° C. to obtain 12.58 kg of Compound (15) (82.9%from aminomethyl ester hydrochloride (4)).

Example 8

Starting material carboxylic acid (13) (5.86 g, 22.3 mmol) was dissolvedin 88 ml of dichloromethane at room temperature, and oxalyl chloride(2.34 ml, 26.7 mmol) and catalytic amount of DMF were added to themixture with ice-cooling. The mixture was stirred for 1 hour at roomtemperature and the solvent was removed under reduced pressure. After115 ml of dichloromethane was added, substituted aniline (5.05 g, 24.5mmol) and triethylamine (4.65 ml, 33.4 mmol) were added. The mixture wasstirred for 2.5 hours at room temperature, and ice water was poured intothe mixture. The mixture was extracted with chloroform, and the organiclayer was washed with water and dried over a hydrous magnesium sulfate.After the solvent was removed under reduced pressure, ethyl acetate andhexane were added to the residue and appeared crystals were collected byfiltration to obtain Amide Compound A (7.00 g, 70% yield).

Example 9

Starting material Carboxylic acid (13) (2.00 g, 7.59 mmol) was dissolvedin 20 ml of ethyl acetate at room temperature, and thionyl chloride(0.61 ml, 8.36 mmol) and catalytic amount of DMF were added to themixture. After the mixture was stirred for 1.5 hours at roomtemperature, the solvent was removed under reduced pressure. After 20 mlof tetrahydrofuran was added to the residue, substituted aniline (1.33g, 7.59 mmol) and triethylamine (3.18 ml, 22.8 mmol) were added. Themixture was stirred for 3 hours at room temperature, and 40 ml of waterwas poured into the mixture. The mixture was ice-cooled and appearedcrystals were collected by filtration to obtain Amide Compound B (2.60g, 81.4%).

¹H NMR (DMSO-d₆): 1.26 (s, 9H), 1.40 (m, 4H), 1.83 (d, J=11.7 Hz, 2H),1.95 (d, J=9.7 Hz, 2H), 2.16 (m, 3H), 3.04 (m, 1H), 3.60 (t, J=5.6 Hz,2H), 3.83 (t, J=2.5 Hz, 2H), 5.83 (m, 2H), 6.77 (dd, J=9.1 Hz, 16.9 Hz,2H), 7.75 (dd, J=2.7 Hz, 9.1 Hz, 1H), 8.26 (d, J=2.7 Hz, 1H), 9.63 (s,1H)

Example 10

Starting material carboxylic acid (13) (316 mg, 1.20 mmol) was dissolvedin 5 ml of DMF at room temperature, and substituted aniline (286 mg,1.20 mmol), N-hydroxybenzotriazole (195 mg, 1.44 mmol) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (276 mg,1.44 mmol) were added to the mixture. After the mixture was stirred for14 hours at room temperature, water was poured into the mixture and themixture was extracted with chloroform twice. The combined organic layerwas washed with brine and dried over sodium sulfate. After the solventwas removed under reduced pressure, methanol was added to the residueand appeared crystals were collected by filtrate to obtain AmideCompound C (195 mg, 33.6%).

¹H NMR (DMSO-d₆): 1.27 (s, 9H), 1.43 (m, 4H), 1.88 (d, J=12.6 Hz, 2H),1.98 (d, J=11.7 Hz, 2H), 2.29 (m, 1H), 3.07 (m, 1H), 6.81 (d, J=8.4 Hz,1H), 7.76 (d, J=8.7 Hz, 2H), 8.13 (m, 3H), 8.23 (dd, J=2.3 Hz, 8.6 Hz,1H), 8.99 (s, 1H), 10.07 (s, 1H)

Example 11

Starting material Carboxylic acid (13) (1.05 g, 4.00 mmol) was dissolvedin 30 ml of ethyl acetate at room temperature, and thionyl chloride (4.5ml, 61.7 mmol) and catalytic amount of DMF were added to the mixture.After the mixture was stirred for 1 hour at room temperature, thesolvent was removed under reduced pressure. Substituted aniline (664.2mg, 3.95 mmol) and 10 ml of pyridine were added to the residue. Themixture was stirred for 4 hours at 60° C., and 50 ml of water was pouredinto the mixture. The mixture was stirred with ice-cooling and theappeared crystals were collected by filtrate to obtain Amide Compound D(2.23 g, 55.5%).

¹H NMR (DMSO-d₆): 1.27 (s, 9H), 1.39 (m, 3H), 1.95 (c, 4H), 2.45 (t,J=11.6 Hz, 1H), 3.10 (m, 1H), 3.34 (m, 1H), 6.83 (d, J=8.6 Hz, 1H), 7.28(td, J=2.7 Hz, 9.1 Hz, 1H), 7.74 (dd, J=4.8 Hz, 8.8 Hz, 1H), 7.88 (dd,J=2.5 Hz, 8.6 Hz, 1H), 12.31 (s, 1H)

Example 12

The following Compounds (XII) are synthesized using NH₂-Z (XI-1) as astarting material in the similar manner to Examples 8 to 11.

INDUSTRIAL APPLICABILITY

Trans-4-amino-1-cyclohexancarboxylic acid derivatives which are usefulas an intermediate of a medicament can be efficiently produced by theprocesses of the present invention. The present invention also providesintermediates which are used for the processes of the present invention.

1. A process for the preparation of a compound of the formula:

wherein R¹ and R² are each independently lower alkyl, comprisingreacting a compound of the formula:

wherein each symbol is the same as defined above, with a base in anaprotic solvent.
 2. The process as claimed in claim 1 comprisingrecrystallizing Compound (I) in an aprotic solvent.
 3. The process asclaimed in claim 1 or 2 wherein the aprotic solvent is a nonpolaraprotic solvent.
 4. The process as claimed in claim 3 wherein theaprotic solvent is toluene.
 5. The process as claimed in any one ofclaims 1 to 4 wherein the base is selected from a group of an aikoxide,and alkaline metal halide and an alkaline metal amide.
 6. The process asclaimed in claim 5 wherein the base is an alkaline metal lower alkoxide.7. The process as claimed in any one of claims 1 to 6 wherein thecompound of the formula:

wherein R¹ and R² are each independently lower alkyl, is prepared byreacting a compound of the formula:

wherein R² is lower alkyl, with a compound of the formula:

wherein R¹ is lower alkyl to obtain a compound of the formula:

wherein each symbol is the same as defined above, and by oxidizingCompound (III).
 8. A process for the preparation of a compound of theformula:

wherein R¹ is the same as defined above, comprising hydrolyzing Compound(I) which is not isolated from a reaction solution.
 9. The process asclaimed in claim 8 comprising hydrolyzing Compound (I) which is notisolated from a reaction solution.
 10. The process as claimed in any oneof claims 1 to 9 wherein R¹ is t-butyl and R² is methyl.